rs2274976

chr1-11790870-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_005957.5(MTHFR):c.1781G>A(p.Arg594Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 1,613,878 control chromosomes in the GnomAD database, including 2,928 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R594W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.044 (231 hom., cov: 33)
  • Exomes 𝑓: 0.053 (2697 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 3.20

Genes affected

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_005957.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0017618239).
• BP6: Variant 1-11790870-C-T is Benign according to our data. Variant chr1-11790870-C-T is described in ClinVar as [Likely_benign, other]. Clinvar id is 194071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11790870-C-T is described in Lovd as [Pathogenic]. Variant chr1-11790870-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.1781G>A	p.Arg594Gln	missense_variant	12/12	ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.1781G>A	p.Arg594Gln	missense_variant	12/12	1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.0443 AC: 6735 AN: 151930 Hom.: 230 Cov.: 33

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0431

GnomAD3 exomes AF: 0.0555 AC: 13949 AN: 251250 Hom.: 651 AF XY: 0.0580 AC XY: 7884 AN XY: 135816

Gnomad AFR exome AF: 0.0282

Gnomad AMR exome AF: 0.0434

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.117

Gnomad SAS exome AF: 0.131

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.0442

Gnomad OTH exome AF: 0.0492

GnomAD4 exome AF: 0.0535 AC: 78138 AN: 1461830 Hom.: 2697 Cov.: 32 AF XY: 0.0552 AC XY: 40131 AN XY: 727222

Gnomad4 AFR exome AF: 0.0256

Gnomad4 AMR exome AF: 0.0428

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.0184

Gnomad4 NFE exome AF: 0.0494

Gnomad4 OTH exome AF: 0.0606

GnomAD4 genome AF: 0.0443 AC: 6739 AN: 152048 Hom.: 231 Cov.: 33 AF XY: 0.0444 AC XY: 3300 AN XY: 74316

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.0431

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.0160

Gnomad4 NFE AF: 0.0463

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0462 Hom.: 487

Bravo AF: 0.0427

TwinsUK AF: 0.0496 AC: 184

ALSPAC AF: 0.0532 AC: 205

ESP6500AA AF: 0.0297 AC: 131

ESP6500EA AF: 0.0462 AC: 397

ExAC AF: 0.0562 AC: 6823

Asia WGS AF: 0.127 AC: 441 AN: 3478

EpiCase AF: 0.0387

EpiControl AF: 0.0410

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 528/13006=4.05% -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2017	- -

MTHFR-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	10
Dann	Benign	0.92
DEOGEN2	Benign	0.13	T;.;.;T;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.065	N
MetaRNN	Benign	0.0018	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N;.;.;N;.;.
MutationTaster	Benign	0.99	P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.4	N;N;N;N;.;.
REVEL	Benign	0.18
Sift	Benign	1.0	T;T;T;T;.;.
Sift4G	Benign	1.0	T;T;T;T;.;.
Polyphen		0.0	B;.;.;B;.;.
Vest4		0.044
MPC		0.30
ClinPred		0.0089	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.042
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2274976; hg19: chr1-11850927; COSMIC: COSV57171488; COSMIC: COSV57171488;